The present invention relates to methods of preparing new taxoids of general formula: 
in which:
Z represents a hydrogen atom or a radical of general formula: 
in which:
R1 represents a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl radicals, a thenoyl or furoyl radical or a radical R2xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94 in which
R2 represents:
an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, a phenyl radical (unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms), cyano radicals, carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms;
a phenyl or an xcex1- or xcex2-naphthyl radical radical, which is unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, and a 5-membered aromatic heterocyclic radical;
R3 represents a phenyl radical;
R4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms in an unbranched or branched chain, this radical being unsubstituted or substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms, or alternatively R4 represents a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms, or alternatively R4 represents a benzoyloxy radical; and
R5 represents an alkoxy radical containing 1 to 4 carbon atoms in an unbranched or branched chain, substituted by an alkylthio radical containing 1 to 4 carbon atoms.
Preferably, the radical R4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms, or a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms.
More especially, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which
R1 represents a benzoyl radical, or a radical R2xe2x80x94Oxe2x80x94C (xe2x95x90O)xe2x80x94 in which
R2 represents a tert-butyl radical, and
R3 represents a phenyl radical, and
R4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 4 carbon atoms, and
R5 represents an alkoxy group containing 1 to 4 carbon atoms substituted by a methylthio radical.
Still more especially, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94 in which R2 represents a tert-butyl radical and R3 represents a phenyl radical, R4 represents an acetoxy, or a methoxyacetoxy radical, and R5 represents a methylthiomethoxy radical.
The products of general formula (I) in which Z represents a radical of general formula (II) display noteworthy anti-tumor and anti-leukemic properties.
According to the present invention, the new products of general formula (I) in which Z represents a radical of general formula (II) may be obtained by esterification of a product of general formula: 
in which R4 and R5 are defined as above, by means of an acid of general formula: 
in which R1 and R3 are defined as above, and either R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or R6 and R7 together form a saturated 5- or 6-membered heterocycle, or by means of a derivative of this acid, to obtain an ester of general formula: 
in which R1, R3, R4, R5, R6 and R7 are defined as above, followed by replacement of the protective groups represented by R7 and/or R6 and R7 by hydrogen atoms.
The esterification by means of a product of general formula (XII):
Rxe2x80x24xe2x88x92X1xe2x80x83xe2x80x83(XII) 
in which Rxe2x80x24 is such that Rxe2x80x24xe2x80x94Oxe2x80x94 is identical to R4 defined as above but cannot represent a hydrogen atom or a hydroxyl radical, and in which X1 represents a hydroxyl radical, may be performed in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between xe2x88x9210 and 90xc2x0 C.
The esterification may also be carried out using a product of general formula (XII) in which X1 represents a radical R4xe2x80x94Oxe2x80x94, working in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between 0 and 90xc2x0 C.
The esterification may also be carried out using a product of general formula (XII) in which X1 represents a halogen atom, in the presence of a base (tertiary aliphatic amine), working in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between 0 and 80xc2x0 C.
Preferably, R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or alternatively R6 and R7 together form a saturated 5- or 6-membered heterocycle.
When R6 represents a hydrogen atom, R7 preferably represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, xcex2-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl radical.
When R6 and R7 together form a heterocycle, the latter is preferably an oxazolidine ring optionally monosubstituted or gem-disubstituted at position 2.
Replacement of the protective groups R7 and/or R6 and R7 by hydrogen atoms may be performed, depending on their nature, in the following manner:
1) when R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, replacement of the protective groups by hydrogen atoms is performed by means of an inorganic acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid) used alone or mixed, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitrites at a temperature of between xe2x88x9210 and 60xc2x0 C.,
2) when R6 and R7 together form a saturated 5-or 6-membered heterocycle, and more especially an oxazolidine ring of general formula: 
in which R1 is defined as above and R8 and R9, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an arylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R8 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted with a trihalomethyl radical such as trichloromethyl and R9 represents a hydrogen atom, or alternatively R8 and R9, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, replacement of the protective group formed by R6 and R7 by hydrogen atoms may be performed, depending on the meanings of R1, R8 and R9, in the following manner:
a) when R1 represents a tert-butoxycarbonyl radical and R8 and R9, which may be identical or different, represent an alkyl radical or an arylalkyl (benzyl) or aryl (phenyl) radical, or alternatively R8 represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and R9 represents a hydrogen atom, or alternatively R8 and R9 together form a 4- to 7-membered ring, treatment of the ester of general formula (V) with an inorganic or organic acid, where appropriate in an organic solvent such as an alcohol, yields the product of general formula (VII): 
in which R3, R4 and R5 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted or by means of thenoyl chloride, of furoyl chloride or of a product of general formula (VIII):
R2xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Xxe2x80x83xe2x80x83(VIII) 
in which R2 is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue xe2x80x94Oxe2x80x94R2 or xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II).
Preferably, the product of general formula (V) is treated with formic acid at a temperature in the region of 20xc2x0 C. to yield the product of general formula (VII).
Preferably, the acylation of the product of general formula (VII) by means of a benzoyl chloride in which the phenyl radical is optionally substituted or by means of thenoyl chloride, of furoyl chloride or of a product of general formula (VIII) is performed in an inert organic solvent chosen from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is performed at a temperature of between 0 and 50xc2x0 C., and preferably in the region of 20xc2x0 C.
b) when R1 represents an optionally substituted benzoyl radical, a thenoyl or furoyl radical or a radical R2Oxe2x80x94C(xe2x95x90O)xe2x80x94 in which R2 is defined as above, R8 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms and R9 represents a hydrogen atom, replacement of the protective group formed by R6 and R7 by hydrogen atoms is performed in the presence of an inorganic acid (hydrochloric acid, sulfuric acid) or organic acid (acetic acid, methanesulfonic acid, trifluoromethane-sulfonic acid, p-toluenesulfonic acid) used alone or mixed in a stoichiometric or catalytic amount, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of between xe2x88x9210 and 60xc2x0 C., and preferably between 15 and 30xc2x0 C.
According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom and R4 and R5 are defined as above, may be obtained from 10-deacetyl-baccatin III of formula (IX): 
It can be especially advantageous to protect the hydroxyl functions at the positions 7 and 13 selectively, for example in the form of a silyl diether which may be obtained by the action of a silyl halide of general formula (X):
(R)3xe2x80x94Sixe2x80x94Halxe2x80x83xe2x80x83(X) 
in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms, optionally substituted with a phenyl radical, or a phenyl radical, on 10-deacetyl-baccatin III, to obtain a product of general formula (XI): 
in which R is defined as above, followed by the action of a product of general formula (XII):
Rxe2x80x24xe2x80x94X1xe2x80x83xe2x80x83(XII) 
in which Rxe2x80x24 is such that Rxe2x80x24xe2x80x94Oxe2x80x94 is identical to R4 defined as above but cannot represent a hydrogen atom or a hydroxyl radical, and XI represents a halogen atom, to obtain a product of general formula (XIII): 
in which R and R4 are defined as above, the silyl protective groups of which are replaced by hydrogen atoms to obtain a product of general formula (XIV): 
in which R4 is defined as above, which is etherified selectively at position 7 by the action of a product of general formula:
Rxe2x80x25xe2x80x94X2xe2x80x83xe2x80x83(XV) 
in which Rxe2x80x25 is such that Rxe2x80x25xe2x80x94Oxe2x80x94 is identical to R5 defined as above and X2 represents a halogen atom or a sulfuric or sulfonic ester residue, to give the product of general formula (III).
Generally, the action of a silyl derivative of general formula (X) on 10-deacetyl-baccatin III is performed in pyridine or triethylamine, where appropriate in the presence of an organic solvent such as an aromatic hydrocarbon, for instance benzene, toluene or xylenes, at a temperature between 0xc2x0 C. and the refluxing temperature of the reaction mixture.
Generally, the action of a product of general formula (XII) on a product of general formula (XI) is performed, after metalation of the hydroxyl function at position 10 by means of an alkali metal hydride such as sodium hydride, an alkali metal amide such as lithium amide or an alkali metal alkylide such as butyllithium, working in an organic solvent such as dimethylformamide or tetrahydrofuran at a temperature of between 0 and 50xc2x0 C.
Generally, the replacement of the silyl protective groups of the product of general formula (XIII) by hydrogen atoms is performed by means of an acid such as hydrofluoric acid or trifluoroacetic acid in the presence of a base such as triethylamine or pyridine optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, the base optionally being combined with an inert organic solvent such as a nitrile, for instance acetonitrile, or a halogenated aliphatic hydrocarbon such as dichloromethane at a temperature of between 0 and 80xc2x0 C.
Generally, the action of a product of general formula (XV) on a product of general formula (XIV) is performed under the conditions described above for the action of a product of general formula (XII) on a product of general formula (XI).
According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II), and R4 and R5 are defined as above may be obtained from a product of general formula (XVI): 
in which R1, R3, R6 and R7 are defined as above, by silylation at position 7 by means of a product of general formula (X), to obtain a product of general formula (XVII): 
in which R, R1, R3, R6 and R7 are defined as above, which is functionalized at position 10 by means of a product of general formula (XII) to give a product of general formula (XVIII): 
in which R, R1, R3, R4, R6 and R7 are defined as above, the silyl protective group of which is replaced by a hydrogen atom to give a product of general formula (XIX): 
which, by the action of a product of general formula (XV), yields the product of general formula (V), the protective groups of which are replaced by hydrogen atoms to give a product of general formula (I) in which Z represents a radical of general formula (II).
The reactions used for silylation, functionalization and replacement of the protective groups by hydrogen atoms are performed under conditions similar to those described above.
The products of general formula (XVI) may be obtained under the conditions described in European Patent EP 0 336 841 and International Applications PCT WO 92/09589 and WO 94/07878, or from the products of general formula (XX): 
in which R1 and R3 are defined as above, according to known methods for protecting the hydroxyl function of the side chain without affecting the remainder of the molecule.
According to the invention, the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) may be obtained by the action of activated Raney nickel, in the presence of an aliphatic alcohol containing 1 to 3 carbon atoms, on a product of general formula (XXI): 
in which R4 is defined as above and Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, an alkynyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 3 to 6 carbon atoms, or alternatively Rxe2x80x2 and Rxe2x80x3, together with the carbon atom to which they are linked, form a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, and Z1 represents a hydrogen atom or a radical of general formula (XXII): 
in which R1 and R3 are defined as above, and either R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or R6 and R7 together form a saturated 5- or 6-membered heterocycle, and R4 is defined as above, to obtain a product of general formula (XXIII): 
in which R1, R3, R4, R5, R6, and R7 are defined as above, followed, when Z1 represents a radical of general formula (XXII), that is to say when the product of general formula (XXIII) is identical to the product of general formula (V), by replacement of the protective groups represented by R6 and/or R6 and R7 by hydrogen atoms under the conditions described above.
Generally, the action of activated Raney nickel in the presence of the aliphatic alcohol is performed at a temperature of between xe2x88x9210 and 60xc2x0 C.
According to the invention, the product of general formula (XXI) in which Z1 and R4 are defined as above may be obtained by the action of a dialkyl sulfoxide of general formula (XXIV): 
in which Rxe2x80x2 and Rxe2x80x3 are defined as above, on a product of general formula (XIX).
Generally, the reaction of the sulfoxide of general formula (XXIV), preferably dimethyl sulfoxide, with the product of general formula (XIX) is performed in the presence of a mixture of acetic acid and acetic anhydride or a derivative of acetic acid such as a haloacetic acid at a temperature of between 0 and 50xc2x0 C., and preferably in the region of 25xc2x0 C.
According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II) may be obtained by the action of a product of general formula (XII) on a product of general formula (XXV): 
in which R1, R3, R5, R6 and R7 are defined as above, working under the conditions described for the action of a product of general formula (XII) on a product of general formula (XI), followed by replacement of the protective groups represented by R7, or R6 and R7, by hydrogen atoms under the conditions described above.
The product of general formula (XXV) may be obtained by the action of a zinc halide such as zinc iodide or hydrazine on a product of general formula (XXVI): 
in which R1, R3, R5, R6 and R7 are defined as above.
Generally, the reaction is performed working in an aliphatic alcohol containing 1 to 4 carbon atoms, such as methanol or ethanol, at a temperature of between 0 and 50xc2x0 C.
The product of general formula (XXVI) may be obtained by the action of activated Raney nickel in the presence of an aliphatic alcohol containing 1 to 3 carbon atoms on a product of general formula (XXVII): 
in which R1, R3, R6, R7, Rxe2x80x2 and Rxe2x80x3 are defined as above, working under the conditions described above for the preparation of a product of general formula (I) from a product of general formula (XXI).
The product of general formula (XXVII) may be obtained by the action of a sulfoxide of general formula (XXIV) on a product of general formula (XXVII): 
in which R1, R3, R6 and R7 are defined as above, working under the conditions described above for the action of a sulfoxide of general formula (XXIV) on a product of general formula (XIX).
The product of general formula (XXVIII) may be obtained from a product of general formula (XXIX): 
in which R1, R3, R6 and R7 are defined as above, working under the conditions described above for replacing the silyl groups of the product of general formula (XIII) by hydrogen atoms.
The product of general formula (XXIX) may be prepared under the conditions described in International Application PCT WO 95/11241.
The new products of general formula (I) obtained by carrying out the processes according to the invention may be purified according to known methods such as crystallization or chromatography.
The products of general formula (I) in which Z represents a radical of general formula (II) display noteworthy biological properties.
In vitro measurement of the biological activity was performed on tubulin extracted from pig""s brain by the method of M. L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). Study of the depolymerization of microtubules to tubulin was performed according to the method of G. Chauvixc3xa8re et al., C.R. Acad. Sci., 293(7): series II, 501-503 (1981). In this study, the products of general formula (I) in which Z represents a radical of general formula (II) were shown to be at least as active as TAXOL(copyright) (paclitaxel) and TAXOTERE(copyright) (docetaxel).
In vivo, the products of general formula (I) in which Z represents a radical of general formula (II) were shown to be active in mice grafted with B16 melanoma at doses of between 1 and 10 mg/kg administered intraperitoneally, as well as on other liquid or solid tumors.
The new products have anti-tumor properties, and more especially activity against tumors which are resistant to TAXOL(copyright) (paclitaxel) or to TAXOTERE(copyright) (docetaxel). Such tumors comprise colon tumors which have a high expression of the mdr1 gene (multiple drug resistance gene). Multiple drug resistance is a customary term relating to the resistance of a tumor to different products having different structures and mechanisms of action. Taxoids are generally known to be strongly recognized by experimental tumors such as P388/DOX, a cell line selected for its resistance to doxorubicin (DOX) which expresses mdr1.